Leveraging the replication-competent avian-like sarcoma virus/tumor virus receptor-A system for modeling human gliomas.

Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion, immune evasion, cellular, and molecular heterogeneity, and resistance to treatments resulting in high rates of recurrence. An extensive understanding of the genomic and microenvironmental landscape of gliomas gathered over the past decade has renewed interest in pursuing novel therapeutics, including immune checkpoint inhibitors, glioma-associated macrophage/microglia (GAMs) modulators, and others. In light of this, predictive animal models that closely recreate the conditions and findings found in human gliomas will serve an increasingly important role in identifying new, effective therapeutic strategies. Although numerous syngeneic, xenograft, and transgenic rodent models have been developed, few include the full complement of pathobiological features found in human tumors, and therefore few accurately predict bench-to-bedside success. This review provides an update on how genetically engineered rodent models based on the replication-competent avian-like sarcoma (RCAS) virus/tumor virus receptor-A (tv-a) system have been used to recapitulate key elements of human gliomas in an immunologically intact host microenvironment and highlights new approaches using this model system as a predictive tool for advancing translational glioma research.

Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment.

Glioblastoma (GBM) is the most common malignant adult brain cancer with no curative treatment strategy. A significant hurdle in GBM treatment is effective therapeutic delivery to the brain-invading tumor cells that remain following surgery within functioning brain regions. Developing therapies that can either directly target these brain-invading tumor cells or act on other cell types and molecular processes supporting tumor cell invasion and recurrence are essential steps in advancing new treatments in the clinic. This review highlights some of the drug delivery strategies and nanotherapeutic technologies that are designed to target brain-invading GBM cells or non-neoplastic, invasion-supporting cells residing within the GBM tumor microenvironment.

An ion-paired moxifloxacin nanosuspension eye drop provides improved prevention and treatment of ocular infection.

There are numerous barriers to achieving effective intraocular drug administration, including the mucus layer protecting the ocular surface. For this reason, antibiotic eye drops must be used multiple times per day to prevent and treat ocular infections. Frequent eye drop use is inconvenient for patients, and lack of adherence to prescribed dosing regimens limits treatment efficacy and contributes to antibiotic resistance. Here, we describe an ion-pairing approach used to create an insoluble moxifloxacin-pamoate (MOX-PAM) complex for formulation into mucus-penetrating nanosuspension eye drops (MOX-PAM NS). The MOX-PAM NS provided a significant increase in ocular drug absorption, as measured by the area under the curve in cornea tissue and aqueous humor, compared to Vigamox in healthy rats. Prophylactic and treatment efficacy were evaluated in a rat model of ocular Staphylococcus aureus infection. A single drop of MOX-PAM NS was more effective than Vigamox, and completely prevented infection. Once a day dosing with MOX-PAM NS was similar, if not more effective, than three times a day dosing with Vigamox for treating S. aureus infection. The MOX-PAM NS provided increased intraocular antibiotic absorption and improved prevention and treatment of ocular keratitis, and the formulation approach is highly translational and clinically relevant.

Preclinical evaluation of a hypotonic docetaxel nanosuspension formulation for intravesical treatment of non-muscle-invasive bladder cancer.

Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure. We compare the bladder residence time and efficacy in an immune-competent rat model of NMIBC to the clinical comparator, solubilized docetaxel (generic Taxotere) diluted for intravesical administration. We found that only the intravesical docetaxel nanosuspension significantly decreased cell proliferation compared to untreated tumor tissues. The results presented here suggest that the combination of nanoparticle-based chemotherapy and a hypotonic vehicle can provide more efficacious local drug delivery to bladder tissue for improved treatment of refractory NMIBC.

Erratum: Author Correction: The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures.

[This corrects the article DOI: 10.1038/s42003-018-0017-7.].

The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures.

The EphA2 receptor tyrosine kinase is capable of activating multiple diverse signaling pathways with roles in processes such as tissue homeostasis and cancer. EphA2 is known to form activated oligomers in the presence of ephrin-A ligands. Here, we characterize the lateral interactions between full-length EphA2 molecules in the plasma membrane in the presence of three types of ligands (dimeric ephrinA1-Fc, monomeric ephrinA1, and an engineered peptide ligand) as well as in the absence of ligand, using a quantitative FRET technique. The data show that EphA2 forms higher-order oligomers and two different types of dimers that all lead to increased EphA2 tyrosine phosphorylation, which is indicative of increased kinase-dependent signaling. We find that different ligands stabilize conformationally distinct oligomers that are assembled through two different interfaces. Our results suggest that these different oligomeric assemblies could have distinct signaling properties, contributing to the diverse activities of the EphA2 receptor.

Mucus-penetrating budesonide nanosuspension enema for local treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder that affects more than 1 million individuals in the USA. Local therapy with enema formulations, such as micronized budesonide (Entocort®), is a common strategy for treating patients with distally active IBD. However, we hypothesize that micronized particulates are too large to effectively penetrate colorectal mucus, limiting the extent of drug delivery to affected tissues prior to clearance. Here, we describe the development of a budesonide nanosuspension (NS) with the appropriate surface coating and size to enhance penetration of colorectal mucus and ulcerated colorectal tissues. We demonstrate that model fluorescent polystyrene (PS) particles ∼200 nm in size with a muco-inert Pluronic F127 coating provide enhanced mucosal distribution and tissue penetration in mice with trinitrobenzenesulfonic acid (TNBS)-induced IBD compared to model 2 µm PS particles coated with polyvinylpyrollidone (PVP), the stabilizer used in the clinical micronized budesonide formulation. We then used a wet-milling process to develop a budesonide NS formulation with a muco-inert Pluronic F127 coating (particle size ∼230 nm), as well as a budesonide microsuspension (MS) stabilized with PVP (particle size ∼2 µm). Using an acute TNBS mouse model of IBD, we show that daily budesonide NS enema treatment resulted in a significant reduction in the macroscopic (decreased colon weight) and microscopic (histology score) symptoms of IBD compared to untreated controls or mice treated daily with the budesonide MS enema. Further, we show that the budesonide NS enema treated mice had a significantly reduced number of inflammatory macrophages and IL-ß producing CD11b + cells in colon tissue compared to untreated controls or mice treated with the budesonide MS enema. We conclude that the nano-size and muco-inert coating allowed for enhanced local delivery of budesonide, and thus, a more significant impact on local colorectal tissue inflammation.

Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.

Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.

Preclinical Evaluation of Intravesical Cisplatin Nanoparticles for Non-Muscle-Invasive Bladder Cancer.

Purpose: Prior clinical trials evaluating cisplatin for non-muscle-invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past.Experimental Design: Cisplatin nanoparticles (CDDP NPs) were developed using biocompatible poly(l-aspartic acid sodium salt; PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG). In vitro cytotoxicity studies confirmed activity of CDDP NPs and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP NPs and CDDP solution were evaluated for bladder absorption in murine models 1 and 4 hours after intravesical administration. In vivo efficacy was evaluated in an immunocompetent carcinogen model of NMIBC.Results: CDDP NPs showed decreased local toxicity, as assessed by bladder weight, compared with CDDP solution. Furthermore, >2 µg/mL of platinum was observed in mouse serum after intravesical administration of CDDP solution, whereas serum platinum was below the limit of quantification after intravesical administration of CDDP NPs. CDDP NPs provided significantly increased (P < 0.05) drug levels in murine bladders compared with CDDP solution for at least 4 hours after intravesical administration. In vivo, CDDP NPs reduced cancer cell proliferation compared with untreated controls, and was the only treatment group without evidence of invasive carcinoma.Conclusions: Cisplatin-loaded PAA NPs have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects. Clin Cancer Res; 23(21); 6592-601. ©2017 AACR.